Guidelines English Module 3 P part - moph · ICH Product evaluation Comments MAQ_R1 Guide for quality submission Module 3 Quality Section Drug Product: 3.2.P ... Q6A ICH Q6B A description

Guide for the Quality Module 3- Part P- Finished Product

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Guide for the Quality Module 3 - Part P

Finished Product

Prepared by the Technical Subcommittee’s experts under the supervision of Dr. Rita Karam, Head of Quality Assurance of Pharmaceutical Products


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Drug Name dosage form & Strength Manufacturer: Applicant: ICH: Quality Guidelines:

Stability Q1A(R2)-Q1B-Q1C-Q1D-Q1E

AnalyticalValidation : Q2(R1)

Impurities: Q3A(R2)-Q3B(R2)-Q3C(R4)

Pharmacopoeias: Q4B with annexes 1 to 12.

Quality of Biotechnological products Q5A(R1)-Q5B –Q5C-Q5D-Q5E

Specifications : Q6A-Q6B

Good Manufacturing Practice : Q7

Pharmaceutical Development : Q8(R2)

Quality Risk Management : Q9

Pharmaceutical Quality System : Q10

Development and manufacture of drug substances Q11

Lifecycle management Q12


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Comments Product evaluation ICH MAQ_R1

Guide for quality submission Module 3 Quality

Section

Drug Product:

3.2.P

The composition (e.g., components of the capsule shell, components of ink used on the drug product) should also be included. If the diluent is co-packaged with the drug product, the information on the diluent should be placed in a separate Drug Product section. The use of an over-fill should be indicated.

ICH Q6A ICH Q6B

A description of the drug product and its composition should be provided. The information provided should include: Description of the dosage form; Composition, Function of the components, and a

reference to their quality standards Type of container and closure used

for the dosage form

Description and Composition of the Drug Product.

3.2.P.1

Q6A and Q6B And Q8(R2)

The Pharmaceutical Development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. The studies described here are

Pharmaceutical development

3.2.P.2


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distinguished from routine control tests conducted according to specifications. In addition , this section should identify and describe the formulation and process attributes (critical parameters ) that can influence batch reproducibility , product performance and drug product quality . Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical Development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the application.

Components of the Drug Product

3.2.P.2.1

The compatibility of the drug substance with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g., water content, solubility, and particle size distribution, polymorphic or solid state form) of the drug substance that can influence the performance of the drug product should be discussed.

Drug Substance.

3.2.P.2.1.1


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For combination products, the compatibility of drug substances with each other should be discussed.

A compatibility studies must be performed.

The choice of excipients listed in 3.2.P.1, their concentration, their characteristics that can influence the drug product performance should be discussed relative to their respective functions.

Excipients 3.2.P.2.1.2

Drug Product 3.2.P.2.2 Some slides from DrSawaya to illustrate:

This section describes how the final formulation was arrived at. It should give a brief history of the development including the failures along the way. We must try to establish that there is a logical and scientific basis for choosing the proposed formulation from pre formulation to formulation to pilot to production. Comparative dissolution test between test product and reference product(on 3 pHs) Comparative dissolution test among strengths (on 3 pHs). • At least 12 units should be used for each profile determination. • The dissolution measurements of the test and reference batches should be made under exactly the same conditions. The dissolution time points for both the profiles should be the same (e.g., for IR products 15, 30, 45, 60 minutes; for ER products 1,2,3,5,and 8 hours). • For products which are rapidly dissolving, i.e., more than 85% in 15 minutes or less, a profile comparison is not necessary. Difference Factor f1 is a measure of relative error between the two

Q8(R2) A brief summary describing the development of the drug product should be provided, taking into consideration the proposed route of administration and usage. The differences between clinical formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate.

Formulation Development.

3.2.P.2.2.1


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curves of dissolution Similarity Factor f2 Using an average difference of 10% between two dissolution profiles at all sampling time points: f2 is about 50 A test batch dissolution is therefore considered similar to that of the reference batch if the f2 value of the two true profiles is not less than 50. • Ideally for curves to be similar: – f1 should be close to 0, and – f2 should be close to 100 • Practical considerations: – f1 between 0 to 15 and – f2 between 50 to 100 Or A summary of dissolution development can be included in 3.2.P.2.2.3, with cross-reference to studies in Module 5, as considered appropriate.

Only in two cases :

-To compensate losses

-For vitamin preparations.

Any overages in the formulation(s) described in 3.2.P.1 should be justified

Overages. 3.2.P.2.2.2

A summary of dissolution development should be included in 3.2.P.2.2.3, with cross-reference to studies in Module 5, as considered appropriate.

Parameters relevant to the performance of the drug product, such as pH, ionic strength, dissolution, re dispersion, reconstitution, particle size distribution, particle size of the

Physiochemical & biological properties.

3.2.P.2.2.3


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lend/granules flow , properties which might affect capsule filling or tableting , aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed

The progress from pre formulation to formulation to pilot to production scale batches should be shown to be logical, reasoned and continuous.

The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Identify critical steps. Identify key validation parameters in term of mixing times , drying times and temperature Where relevant, the method of sterilization should be explained and justified. Differences between the manufacturing process (es) used to produce pivotal clinical batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.

Manufacturing process development.

3.2.P.2.3

Connections with stability 3.2.P.8

The suitability of the container closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the drug product should be discussed. This discussion should consider, e.g., choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form

Container closure system.

3.2.P.2.4


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(including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).

Connections with stability 3.2.P.8

Q4B ANNEX 4A(R1) Q4B ANNEX 4B(R1) Q4B ANNEX 4C(R1)

Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.

Microbiological attributes.

3.2.P.2.5

There should be a separate Drug Product (diluent) section for co-packaged diluents. Choice and development of co-packaged diluents should be included.

The compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labeling.

Compatibility. 3.2.P.2.6

Manufacture 3.2.P.3 The name, address, and responsibility

of each manufacturer, including contractors, and each proposed

Manufacturer(s) .

3.2.P.3.1


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production site or facility involved in manufacturing and testing should be provided.

Q8(R2) A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.

Batch Formula.

3.2.P.3.2

Q6B Q8(R2)

A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. A narrative description of the manufacturing process, including packaging that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity, where relevant. Steps in the process should have the

Description of Manufacturing Process and Process Controls

3.2.P.3.3


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appropriate process parameters identified, such as time, temperature, or pH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g., low humidity for an effervescent product) should be stated. Proposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3). Additionally for Biotech see 3.2.A.1 for facilities , if appropriate .

Q2A Q2B Q6A Q6B

Critical Steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled. Intermediates: Information on the quality and control of intermediates isolated during the process should be provided.

Control of Critical steps& intermediates.

3.2.P.3.4

Content of process validation protocol: -Short description of the process with a summary of the critical processing steps. -Drug product specifications (at release).

Q6B Description, documentation, and results of the validation and/or evaluation studies should be provided

Process validation

3.2.P.3.5


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-Details of the analytical methods. -Acceptance criteria -sampling plan (where, when and how samples are taken). -details of the methods of recording and evaluation results. -proposed time frame. -batch analytical data. -certificate of analysis. -batch production record -report on unusual findings , modifications or changes found necessary with appropriate rational -conclusion

for critical steps or critical assays used in the manufacturing process (e.g., validation of the sterilisation process or aseptic processing or filling). Viral safety evaluation should be provided in 3.2.A.2, if necessary.

Control of Excipients

3.2.P.4

Certificates of analysis(COA)s from quality control lab(applicant) and from suppliers(vendors) must be provided.

Q6A and Q6B

The specifications for excipients should be provided.

Specifications. 3.2.P.4.1

Q2A and Q6B

The analytical procedures used for testing the excipients should be provided, where appropriate.

Analytical Procedures.

3.2.P.4.2

Q2A, Q2B, and Q6B

Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate.

Validation of Analytical Procedures

3.2.P.4.3

Q3C and Q6B

Justification for the proposed excipient specifications should be provided, where appropriate.

Justification of specifications.

3.2.P.4.4

Certificate of TSE/BSE, presence or absence should be provided from suppliers.

Q5A, Q5D,

For excipients of human or animal origin, information should be provided

Excipients of Human or

3.2.P.4.5


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and Q6B

regarding adventitious agents (e.g., sources, specifications; description of the testing performed; viral safety data). (Details in 3.2.A.2).

Animal Origin.

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For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterization, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format. (Details in 3.2.A.3).

Novel Excipients.

3.2.P.4.6

Control of Drug Product

3.2.P.5

Are the specifications coherent with the dosage form proposed? Is there any differentiation between release specifications and shelf-life ones , specially related to "assay" and related substances content" parameters?

Q3B, Q6A and Q6B

The specification(s) for the drug product should be provided.

Specification(s)

3.2.P.5.1

Q2A and Q6B

The analytical procedures used for testing the drug product should be provided.

Analytical Procedures.

3.2.P.5.2

Validation protocols and reports, with acceptance and rejection criteria and specifications and experimental data, for all analytical chemistry methods developed and used for the characterization of a drug substance and proposed drug product are to be

Q2A, Q2B and Q6B

Analytical validation information, including experimental data, for the analytical procedures used for testing the drug product, should be provided.

Validation of Analytical Procedures.

3.2.P.5.3


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included within the designated sections. These methods may include, but are not limited to (i) identity assays for a drug substance, intermediates, and excipients; (ii) content assays for a drug substance, intermediates, and excipients; (iii) impurity profiling and quantification assays for a drug substance and proposed drug product; (iv) dissolution assays for a proposed drug product or drug products if more than one is included in the marketing application; and (v) stability-indicating assays for a drug substance and proposed drug product The report, data sheets and typical chromatograms should be provided.

Signed COAs for the submission batches should be provided. Typical spectrums (IR/UV) and chromatograms for the relevant tests (HPLC) are required.

Q3B, Q3C, Q6A, and Q6B

A description of batches and results of batch analyses should be provided.

Batch Analyses

3.2.P.5.4

Q3B, Q5C, Q6A, and Q6B

Information on the characterization of impurities should be provided, if not previously provided in "3.2.S.3.2 Impurities".

Characterization of Impurities.

3.2.P.5.5

Q3B, Q6A,

Justification for the proposed drug product specification(s) should be

Justification of

3.2.P.5.6


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and Q6B

provided. Specification.

Q6A and Q6B

Information on the reference standards or reference materials used for testing of the drug product should be provided, if not previously provided in "3.2.S.5 Reference Standards or Materials".

Reference standards or materials.

3.2.P.6

Certificates of analysis from quality control lab (in-house) and from suppliers(vendors) must be provided.

A description of the container closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendia methods (with validation) should be included where appropriate. For non-functional secondary packaging components (e.g., those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided. Suitability information should be located in 3.2.P.2.

Container Closure System.

3.2.P.7

Some slides from Dr. Sawaya to illustrate:

Stability : 3.2.P.8


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Look for more details in 3.2.P.8.3


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IF • Long‐term and accelerated data showing little or no change over time and little or no variability Than • Extrapolation of re‐test period or shelf life beyond the period covered by long‐term data can be proposed. • The proposed re- test period or shelf life can be UP to TWICE, but should not be more than 12 months beyond the period covered by long‐term data (X). ( Max: X + 12 months).

Q1A, Q1D, Q1B, Q3B, and Q5C, Q6A

The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.

Stability Summary and Conclusion

3.2.P.8.1

IF • At the time of submission:

Q1A and

The post-approval stability protocol and stability commitment should be

Post-approval Stability

3.2.P.8.2


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At least 2 pilot scale batches + 1 “lab scale“ � Accelerated studies up to 6 months � Long term up to 12 months Than Stability Commitment: . to continue the stability studies post approval � to place the first 3 production batches on stability studies. • After a new product is approved: � First 3 production batches: 1. Accelerated studies 2. Long term studies through the proposed shelf life. Thereafter, one batch per year. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program.

Q5C provided. Protocol and Stability Commitments.

Example of stability data sheet:

Stability testing of FP may involve monitoring: • appearance • loss of API • formation of degradation products (ICH Q3B), • changes in drug disintegration and dissolution, • loss of package integrity, • Microbial contamination. • Some specifications parameters depend on pharmaceutical form – Tablets: dissolution (or disintegration if justified), water content, hardness, friability…

Q1A, Q1B, Q1C, Q1D, Q2A, Q2B Q3B and Q5C

Results of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, and narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.

Stability Data 3.2.P.8.3


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-Hard gelatin capsules: brittleness, dissolution (or disintegration if justified), water content and microbial bio burden.

-softgelatin capsules: dissolution(or disintegration if justified), microbial bioburden, pH , leakage , and pellicle formation.

-Emulsions:phase separation , pH , viscosity , microbial bioburden, mean size and distribution of dispersed globules.

– Oral solutions and suspensions: formation of a precipitate, clarity for solutions, pH, viscosity, microbial bio burden, extractable , leachable, polymorphic conversion when applicable. Additional tests for suspensions include redispersability, rheological properties , mean size , and distribution of particles. – Small-Volume Parenterals: Color , Clarity of solutions, particulate matter , pH, sterility , endotoxins . Powder for injectable solution: color, reconstitution time, water content. After reconstitution: clarity, color, pH, particles, sterility, endotoxins/pyrogens, and particulate matter. Suspensions for injection should include additional particle size distribution, re dispersability , and rheological properties. Emulsions for injection should include phase separation, viscosity , mean size , and distribution of dispersed globules. -Large-Volume Parenterals: Color , Clarity of solutions, particulate matter , pH, sterility , endotoxins/pyrogens , and volume. -Suppositories: softening range , dissolution at 37degreesC.


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Bracketing

-Topical ,ophthalmic, and otic preparations: Clarity, homogeneity, pH , resuspendability (for

lotions), consistency , viscosity, microbial bio burden , and water loss should be tested. For ophthalmic and otic products additional attributes should include sterility, particulate matter and extractable.

-Metered-Dose inhalers and Nasal Aerosols: content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate , microbial bio burden, valve delivery , extractable , leachable from plastic and elastomeric components.

The batches must have same: 1. Formula 2. Packaging 3. Raw material source 4. Manufacturing process If one of these parameters change : other stability studies are required. In some cases , we can use : • Bracketing : – bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. – The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested.


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Matrixing

And : Matrixing Design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly, in some cases, different container closure systems. When a secondary packaging system contributes to the stability of the drug product, matrixing can be performed across the packaging systems. Each storage condition should be treated separately under its own matrixing design.

NB: If we have real stability data for only two Real Stability 3.2.P.8.3.1


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commercial batches and if the active ingredient is stable and if the dosage form is conventional we can accept. NB: For an injectable liquid which is stable at refrigerator storage conditions 5degrees+/-3 degrees for long term, we can accept it , even if it is not conform for accelerated : 25degrees+/- 2degrees .

Data.

Definitions of significant changes of data stored at accelerated conditions API Significant change is defined as failure to meet the specification Drug product 1. A 5% potency change from the initial assay value; 2. Any specified degrading exceeding its acceptance criteria 3. Failure to meet acceptance criteria for appearance and physical properties (e.g., color, phase separation, resuspendability, delivery per actuation, caking, hardness); and as appropriate to the product type; 4. The pH exceeding its acceptance criteria; and 5. Dissolution exceeding the acceptance criteria for 12 dosage units.

Accelerated Stability.

3.2.P.8.3.2


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Critical Remarks:

Some problems found:

-The stability data for long term conditions are provided completely for three batches but one bath has expiration date sixth months later!

- Stability data for three commercial batches are provided for 6 months of accelerated conditions and only for 6 months long term.(not complete)

- The quantity (pilot batch) followed for stability data for each conditions (less than 10% of the commercial or production batch).

-The protocol of stability and annexure are not provided.

- There is no comparison with the innovator drug, that we do not Know it sometimes.

- There is no pharmaceutical or formulation development.

- There is no description of excipients compatibility.

-Parts are not provided: all the 3.2.P.5- Appendix about specifications and analytical methods –the tests procedures and results for packaging materials-

-No dissolution tests studies.

-No certificates of analysis, or not signed.

-No excipient in the formulation but it is mentioned in the leaflet!

-In sterilization, heat penetration studies provided for another product.

-Several tape mistakes: for example: for suppositories, they mention appearance of tablets…

-Data are missing on paper and we must find them on the CD rom or vice versa.

Recommendations:

The part P of module 3will be:

Approve or not or on "Pending" for clarifications and more information or details.


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ANNEXES Brief Summary of the ICH Guidelines for testing of Drug Substances and New drug Products :

Examples of stability data sheet:


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Documents

Guidelines English Module 3 P part - moph · ICH Product evaluation Comments MAQ_R1 Guide for quality submission Module 3 Quality Section Drug Product: 3.2.P ... Q6A ICH Q6B A description